Head of EM
Division, The Sussex Centre for Advanced
Microscopy, School of Life Sciences, University of Sussex, Falmer, Brighton
BN1 9QG, U.K.
Tel: 01273-877585 (direct line) Fax: 01273-678433
Email:
J.R.Thorpe@sussex.ac.uk
and home page.

Summary
of Our Published Research into Pin1's Involvement in Neurodegeneration

(Our
group's articles in bold/CAPS)

The peptidyl-prolyl cis-trans isomerase
protein Pin1 modulates the activity of a range of proteins involved in the
cell cycle, transcription, translation, endocytosis, apoptosis and cytoskeletal
stability via binding phospho-Ser/Thr-Pro motifs (see
Table of Pin1 target proteins). The isomerisation of such
phospho-peptidyl-prolyl bonds by Pin1, at the interface of specific kinase and
phosphatase activities, can provide a novel signalling mechanism regulating
dephosphorylation of specific targets in subcellular compartments. Thereby, Pin1
modulates a range of cellular activities.

We and others had previously demonstrated neuronal Pin1 deficits in
Alzheimer’s Disease (AD; Lu
et al., 1999 ; THORPE
ET AL., 2001) and our overall hypothesis was that such deficits might also occur in
the FTD-tauopathies.

During
this project, we
have acquired data from a range of FTD cases which showed a redistribution of
neuronal Pin1 from nuclei to the cytoplasm, with associated decreases in nuclear
Pin1. Concomitant with this were significantly higher levels of recombinant
Pin1 binding to (its non Pin1-bound, phosphorylated target proteins in) neurons,
indicative and supportive of an endogenous Pin1 shortfall. This was true for the
two non-tauopathy, as well as the six tauopathy, FTDs examined, indicating that
phosphorylations other than of tau can effect this Pin1 redistribution.
Immunoblotting analyses showed a strong association of Pin1 with the
cytoskeletal fraction in all cases. We suggested that this Pin1 redistribution
was an active and relatively early event in response to phosphorylation events
during neurodegeneration (THORPE
ET AL., 2004).

Our overall initial hypothesis was therefore
confirmed and our supposition that the observed Pin1 deficits would be
deleterious to neuronal function has seemingly been vindicated by the finding
that Pin1 gene promoterpolymorphisms,
which result in reduced protein expression, have been found to correlate with AD
(Segat et al.,
2007), though this is contentious [Lambert
et al., 2006; Nowotny
et al., 2007]). Also,
very recent data from a Drosophila tauopathy
model (Khurana et al.,
2006)suggest that tau phosphorylation is
upstream of cell cycle activation; this would lend more support to our hypothesis that shortfalls
of endogenous Pin1 would be deleterious to neuronal function, rather
than the opposing view that Pin1 might instigate neurodegeneration via cyclin D1
(and thence cell cycle) activation (Hamdane
et al., 2002).

We have also studied the non-tauopathy, Neuronal Intermediate Filament Inclusion
Disease (NIFID) in more detail and determined that the intranuclear
inclusions were ultrastructurally and immunologically distinct from cytoplasmic
inclusions, suggesting that abnormal protein aggregation follows separate
pathways in different neuronal compartments (MOSAHEB
ET AL., 2005).

In ageing normal neurons we also observed a
novel association of Pin1 protein with lipofuscin (HASHEMZADEH-BONEHI
ET AL., 2006); the highest levels of endogenous neuronal Pin1
protein were seen to associate with granules of this age-related pigment.
On the basis of the evidence of our data, we hypothesised that this association
might result from oxidative stress effects upon the protein with ageing and/or
neurodegeneration and its resultant clearance through the endo-/lysosomal
pathway; this latter could account for our observed deficits of the protein. Interestingly, the apparent
time-of-onset of our observed neuronal Pin1 shortfalls equates to late middle age, when both
lipofuscin accumulations become significant and susceptibility to late-onset
neurodegenerative diseases occurs.We
suggested that our
data were
consistent with the possibility that neuronal Pin1 deficits may be a
contributory factor in neurodegeneration associated with ageing.

Very
notably, in regard to this
latter point, it has recently been shown that Pin1 is oxidatively modified in
MCI hippocampus, and the authors concluded that the oxidative inactivation of
Pin1 could be involved in the progression from MCI to AD (Butterfield
et al., 2006)

All the above data would suggest that neuronal Pin1
shortfalls may be a susceptibility factor for both neurodegeneration and
ageing...........

(2) HASHEMZADEH-BONEHI
ET AL., 2006:Ageing
leads to oxidative inactivation of Pin1, its clearance through the
endo-/lysosomal pathway and accumulation in ageing-associated lipofuscin. This
could progressively drain available Pin1 and be deleterious to neuronal
function, especially as ageing-related neuronal nuclear Pin1 deficits onset in
late middle age, when both lipofuscin accumulations become significant and
susceptibility to neurodegenerative diseases occur.